Phenylketonuria (PKU) leads to severe neurological disorders in childhood, shunned by the diet. The long-term prognosis after diet diversification at adolescence is uncertain. We report a case of cortical blindness in a young patient regressive 1 month after the diet was resumed.

Mr M., 25 years old, had PKU detected at birth. He maintained good serum levels of Phenylalanine (Phe) (120–300 μmol/L) during childhood and got a normal intellectual development. During adolescence he diversified his diet but maintained low meat and fish intake; Phe was ~1,200 μmol/L with no symptoms. In 2009, the patient stopped the low-Phe amino acid substitutes due to weariness. On June 27, 2011, he consulted for a decrease of visual acuity progressing for 6 months. Ophthalmologic examination found that visual acuity was 2/10 in two eyes associated to a central visual field defect. The visual evoked potentials were altered. MRI showed bilateral and symmetric occipital FLAIR hyperintensities. On admission in the Nutrional Unit on June 29, 2011, blood pressure was 120/70 mmHg, there was no other neurological abnormality. Phe was at 1,512 μmol/L, and not responsive to BH4. He was then treated with a very low-Phe diet with an amino acid substitute, and he obtained Phe between 120 and 300 μmol/L. Visual acuity was suddenly restored on August 1, 2011, with a dramatic attenuation of the MRI hyperintensities.

Our observation shows that the withdrawal of the diet and substitutes exposes to serious neurological complications in adults that may reverse with a fast nutritional support.

Aicardi‐Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon α metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1).

Methods

A genome‐wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families.

Results

Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14–21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD‐unit support interval.

Conclusions

We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.

Truncating mutations were found in the PHF8 gene (encoding the PHD finger protein 8) in two unrelated families with X linked mental retardation (XLMR) associated with cleft lip/palate (MIM 300263). Expression studies showed that this gene is ubiquitously transcribed, with strong expression of the mouse orthologue Phf8 in embryonic and adult brain structures. The coded PHF8 protein harbours two functional domains, a PHD finger and a JmjC (Jumonji-like C terminus) domain, implicating it in transcriptional regulation and chromatin remodelling. The association of XLMR and cleft lip/palate in these patients with mutations in PHF8 suggests an important function of PHF8 in midline formation and in the development of cognitive abilities, and links this gene to XLMR associated with cleft lip/palate. Further studies will explore the specific mechanisms whereby PHF8 alterations lead to mental retardation and midline defects.

We report a patient with an undetermined leucodystrophy associated with type 1A oculocutaneous albinism (OCA). Type 1 OCA results from recessive mutations in the tyrosinase gene (TYR) located in 11q14.3. The patient was found by FISH to carry a deletion of at least the first exon of the TYR gene on one chromosome and a (TG) deletion at codon 244/245 on the second chromosome. The existence of the microdeletion suggested that a gene responsible for leucodystrophy was located in the vicinity of the TYR gene. A combination of a test of hemizygosity and contig mapping studies allowed us to map the gene within a 0.6 cM region flanked by microsatellite markers D11S1780 and D11S931. Keywords: leucodystrophy; oculocutaneous albinism; 11q14 deletion; physical mapping